The most common treatment for newly diagnosed glioblastoma (GBM) is surgical debulking of tumor followed by radiation therapy (RT) and chemotherapy with the DNA alkylator temozolomide (TMZ). Average survival for GBM patients treated in this manner is approximately 15 months, which is a time during which their tumor will recur, and no treatment has been identified that significantly improves the survival of patients with recurrent tumor. A central hypothesis associated with the studies proposed herein is that RT + TMZ therapy causes mutations in GBM, and that improved treatment of recurrent GBM requires a detailed understanding of these mutations. The research associated with this proposal will generate, characterize, and validate recurrent RT modified, TMZ modified, and RT + TMZ modified GBM tumor models that can be used by the principal investigator and others interested in the study and treatment of recurrent GBM.